11,12-DIHYDRODIBENZ{8 b,f{9 AZOCIN-6(5H)-ONES

ABSTRACT

5-(1-Hydrocarbon-3-pyrrolidinyl)-11,12-(dihydro- and dehydro)dibenz(b,f)azocin-6(5H)-ones exhibiting antidepressant activity are disclosed.

United States Patent Helsley 51 July 11, 1972 [54] 1l,12-DIHYDRODIBENZ[B,F]AZOCIN- 6(5H)-ONES [72] Inventor: Grover Cleveland Helsley, Richmond, Va.

[73] Assignee: A. H. Robins Company, Incorporated,

Richmond, Va.

[51] Int. Cl. ..C07d 41/08 [58] Field of Search [56] References Cited UNITED STATES PATENTS 3,454,561 7/1969 Schmutz et al ..260/239.3 T

FOREIGN PATENTS OR APPLICATIONS 1,817,016 8/1969 Germany ..260/239.3 T

OTHER PUBLICATIONS Monro et al. J. Med. Chem." Vol. 6 pages 255- 261 (1963) Sowinski et al. ArzneimitteI-Forsch" No. 5 pages 1 l7- 1 19 (1964) Primary Examiner-Henry R. J iles Assistant Examiner-Robert T. Bond Attorney-G. William King and Norman D. Dawson 5 7] ABSTRACT 5-( l-Hydrocarbon-3-pyrrolidinyl)-1 1,12-(dihydr0- and dehydro )dibenz[ b,fe[azocin-6( 5H )-ones exhibiting amide pressant activity are disclosed.

4 Claims, N0 Drawings ll l Z-DIHYDRODIBENZ[B,F]AZOCIN 6(5H)-ONES U II R Formula I wherein;

R is selected from the group consisting of hydrogen, loweralkyl and phenyllower-alkyl,

Y is selected from CH CH and -Cl-[ CH, and

non-toxic pharmaceutically acceptablly acid addition salts thereof.

The novel compounds of the invention were administered to mice intraperitoneally and the effectiveness of the compounds in blocking the depressant effects which are induced in'mice by intravenous administration of 2 -oxo-3-isobutyl9,l0- dimethoxy-l ,2,3,4,6,7hexahydro-l lbh-benzo[a]quinolizine (tetrabenazine) was determined. The procedure used was a modification of the procedure given by Englehardt, E. L., et al., J. Med. Chem. ll (2): 325(1968). Among thenovel compounds of the present invention which have been shown to block the depressant activity of tetrabenazine when administered intraperitoneally to mice, the compoundsof Examples l, 2, and 3; namely, 5-(l-benzyl-3-pyrrolidinyl)-l l,l2- dihydrobenz[b,f]azocin-6(5H one, 1 l, l 2-dihydro-5 3-pyrrolidinyl)dibenz[b,f]azocin-6(5H)-one, and 5-(l methyl-3- pyrrolidinyl)-l l l 2-dihydrobenz[b,f]azocin-6(5l-l)-one are preferred. TheED s of Example 1, 2 and 3 are l 1.0, 14.5 and 11.7 mg./kg. respectively as determined by, the method of Litchfield and Wilcoxon, J. Pharmacol. Exp. Therap. 96, 99 (1949).

It is, therefore, an object of the present invention to provide novel 5-( l-hydrocarbon-3-pyrrolidinyl)-l l l Z-(dihydroand dehydro)dibenz[b,fe[azocin-6-(5H)-ones. A further object is to provide novel 5-( l-hydrocarbon-3-pyrrolidinyl)-l l,l2- 50 (dihydroand dehydro)dibenz[b,f]azocin-6(5H)-ones having a high degree of antidepressant activity. A still further object is to provide methods for producing the novel compounds, pharmaceutical compositions containing said compounds as active ingredient and methods for the utilization thereof. Additional objects will be apparent to one skilled in the art and still other objects will be apparent hereinafter.

The term lower-alkyl" as used in the specification and claims includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.

' The term phenyllower-alkyl" includes groups such as benzyl, phenethyl, methylbenzyl, phenylpropyl, and the like.

The compounds of the invention are most conveniently employed in the form of non-toxic acid addition salts. Such salts have improved water solubility over the free base. Although the non-toxic salts are preferred, any salt may be prepared for use as a chemical intermediate, as in the preparation of another acid addition salt suitable for administration to an animal .body for the desired physiological effect thereof. Appropriate acid addition salts are those derived from inorganic acids such as hydrochloric, ,hydrobromic, sulfuric and phosphoric, and organic acids such as acetic, citric, lactic, maleic, oxalic, fumaric and tartaric. The preferred addition salt is the hydrochloride. The acid addition salts of the product compounds are conventionally prepared by reaction of the basic compounds with the acid, either or both of which may be in the form of ether, alcohol or acetone solutions.

The starting materials used in preparing the novel compounds of Fonnula I are the compounds of Formula ll,

wherein Y is defined above, namely, 1 1,12- dihydrodibenz[b,f]6( 5H)-one and l 1,12- dehydrodibenz[b,f]6(5H)-one which are prepared according to the procedures described in J. Med. Chem. 6, 258

( 1963) and Arzneimittel-Forsch 5, 117-119(1964) respec- Formula II The preparation of the novel 5-( l-hydrocarbon-3-pyrrolidinyl)-l 1,12-(dihydroand dehydro)dibenz[ b,f]azocin-6( 5 H)- ones (I) may be accomplished by mixing and reacting a selected l-hydrocarbon-3-pyrrolidinol ester (Ill) with a l 1,12- (dihydroand dchydro) dibenz[b,f]azocin-6(5l-l)-one (ll). The reaction sequence is illustrated by the following:

wherein Y and R are asdefined above (R cannot be hydrogen) and Z is halogen, preferably bromine and chlorine or an arylsulfonyloxy group. When his desired to prepare a compound of Formula I wherein R is hydrogen, said compound is prepared by the further step of hydrogenolysis as illustrated by the following:

(l) lllzbulh, I I (In) The hydrogen atom of the secondary amine group of the 5- (3-pyrrolidinyl)-l l,l2-(dihydroand dehydro)dibenz[b,f]-6 (5H)-ones (Ia) exhibits all the reactive characteristics of a secondary group and enters readily into conventional halogen displacement reactions. Thus, additional novel compounds of Formula I can be readily prepared by reacting a compound of Formula la with a reactive halogen compound as shown by the wherein R is as defined (R l-l) and X is a halogen atom, preferably bromine or chlorine.

A general method for the preparation of the novel compounds of Formula] is as follows:

A stirred suspension of a metal hydride or a metal amide as, for example, sodium hydride, in a suitable solvent such as dimethylformamide is treated with a solution of an 1l,l2dihydrodibenz[]azocin-6(5l-l)-one (11) or a solution of an l1,l2-dehydrodibenz[b,f]azocin-6(5l-l)-one (II) in dimethylformamide and the stirred mixture is heated at a temperature of from about 30 C. to about 70 C., preferably at about 40 to 50 C. until the evolution of gas ceases. A solution of the l-hydrocarbon-3-pyrrolidinol ester (III) in dimethylformamide is added slowly to the stirred mixture which is then heated at a temperature of from about 50 C. to about 100 C., preferably at about 70 to 80 C. for a period of from about 4 hours to about 16 hours. The cooled reaction mixture is diluted with water and the solution extracted several times with a suitable organic solvent such asbenzene. The combined extracts are washed with water, dried over a suitable inorganic drying agent, and the solvent evaporated from the dry solution. The residual material is purified by crystallization from a suitable solvent if it is a solid or it is converted to a suitable acid addition salt which is purified by crystallization.

The following examples are given by way of illustration only and are not to be construed as limiting the invention thereto.

EXAMPLE 1 To a stirred suspension of 2.4 g. (0.10 mole) of sodium hydride in 60 ml. of dimethylformamide was added slowly a warm solution of 19.0 g. (0.085 mole) of 11,12- dihydrodibenz[b,f]azocin-6(5l-l)-one in 300 ml. of dimethylformamide. The mixture was stirred at 4050 C. until the evolution of gas ceased (ca. 30 minutes). To the reaction flask was then added slowly 27.0 g. (0.085 mole) of the benzenesulfonate ester of l-benzyl-3-pyrrolidinol dissolved in 50 ml. of dimethylformamide. The stirred mixture was heated at 70-80 C. for 16 hours. The cooled mixture was treated with 700 ml. of water, extracted with benzene and the combined benzene extracts were washed with water, dried over magnesium sulfate and the benzene evaporated from the dried solution at reduced pressure. The residual oil was taken up in isooctane from which 2.0 g. of crystalline material separated and was identified as unreacted 11,12 -dihydrodibenz [b,f]azocin-6 (5H)-one. The isooctane filtrate was evaporated and the residual oil was converted to an amorphous hydrochloride salt which weighed 26.0 g. (71 percent yield). The amorphous hydrochloride salt was converted to the free base with sodium bicarbonate which was treated with oxalic acid to give the oxalate salt. The oxalate salt melted at 8589 C. after it was recrystallized from a methyl ethyl ketone-isopropyl ether mixture.

Analysis: Calculated for C,,,H, N,O C.68.55; H,6.l6; N,5.7l Found: C,68.96; H,6.02,

EXAMPLE 2 5-( l-Methyl-3-Pyrrolidinyl)-l l, l 2-Dihydrodibenz[b,f ]Azocin-6(5H)-One To a stirred suspension of 1.7 g. (0.070 mole) of sodium hydride in 60 ml. of dimethylformamide was added slowly a solution of 13.0 g. (0.058 mole) of ll,l2-dihydrodibenz[b,f] azocin-6(5l-l)-one in 125 ml. of dimethylformamide. The mixture was stirred at 4050 C. until the evolution of gas ceased (ca. minutes). To the reaction flask was then added 14.0 g. (0.058 mole) of the benzenesulfonate ester of l-methyl-3-pyrrolidinol dissolved in 25 ml. of dimethylformamide. The stirred mixture was heated at 6070 C. for 8 hours. The

cooled mixture was treated with 500 ml. of water and extracted with benzene and the combined benzene extracts were washed with water, dried over magnesium sulfate and the solvent evaporated from the dried solution at reduced pressure. The residual oil crystallized on trituration with isooctane and the solid was recrystallized from an isooctane-isopropyl ether mixture yielding 7.5 g. (42 percent) of white product which melted at 1 l6l20 C.

Analysis:

Calculated for c H,,N,o= C,78.39; H,7.24; N,9.l4

Found: C,78.36; H,7.21; N,8.87

EXAMPLE 3 1 l,12-Dihydro-5-(3-Pyrrolidinyl)dibenz[b,f]Azocin-6(5H)- One A solution of 20.0 g. of 5-(l-benzyl-3-pyrrolidinyl)-l1,12- dihydrodibenz[b,f]6(5l-l)-one hydrochloride in 200 ml. of percent ethanol containing ca. 5 g. of 10 percent palladium-on-charcoal catalyst and was shaken in a hydrogen atmosphere at (50-70 C. until one equivalent of hydrogen was absorbed. The cooled suspension was filtered and the filtrate concentrated at reduced pressure. The viscous residual oil was treated with 10% sodium carbonate solution and the basic solution extracted with benzene. The combined benzene extracts were washed with water, dried over magnesium sulfate and the solvent evaporated from the dried solution. The residual oil crystallized on trituration with isooctane and weighed 8.1 g. (58 percent yield); it melted at l l5l 19 C. The product melted at 1 l8-120 C. after it was recrystallized from an isooctane-isopropyl ether mixture.

Analysis: Calculated for C H NO: N,9.S8

Found: C,78.09; H,6.96; N,9.50

EXAMPLE 4 EXAMPLE 5 5-( l-Benzyl-3-Pyrrolidinyl)-l l, l 2-Dehydrobenz[ b,f]Azocin- 6-(5H)-One Utilin'ng the procedure of Example 1, 11,12-dehydrodibenz [b,f]azocin-(5l-l)-one is reacted with the benzene sulfonate ester of 1-benzyl-3-pyrrolidinol to produce the free base of the above title compound.

EXAMPLE 6 5-( l-Methyl-3Pyrrolidinyl)-l l, l 2Dehydrodibenz[b,f]Azocin- 6(5l-l)-One Utilizing the procedure of Example 2, ll,l2-dehydrodibenz [b,f]azocin-(5l-l)-one is reacted with the benzenesulfonate ester of l-methyl-3-pyrrolidinol to produce the title compound.

EXAMPLE 7 5-( 3-Pyrrolidinyl)-l 1, l 2-Dehydrodibenz[ b,f]Azocin-6( 51-1 One Utilizing the procedure of Example 3,5-( l-benzyl-3-pyrrolidinyl)-l1,12-dehydrodibenz[b,f]azocin-6(5l-l)-one is debenzylated to product the title compound.

-( l-Phenylpropyl-3Pyrrolidinyl-l 1,l2-Dehydrodibenz[b,f ]Azocin-6(5l-l)-One Utilizing the procedure of Example 4, 5-(3-pyrrolidinyl)- l l,l2-dehydrodibenz[b,f]azocin-6(5H)-one is reacted with phenyl propyl bromide to produce the title compound.

Effective quantities of any of the foregoing pharmacologically active compounds of Formula I may be administered to a living animal body for therapeutic purposes according to usual modes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules.

Amphetamines and barbiturates are frequently useful in depression therapy as well as tranquilizers. In particular, the use of tranquilizing drugs as with sedatives and the amphetamine group have shown valuable results, especially with disturbed and agitated cases of depression. This invention is, therefore, intended to encompass the combined use of the foregoing with the antidepressant compounds hereof, as well as with other drugs used adjunctively in depression control and treatment. Thus, the compounds of this invention may be administered alone or in combination with other pharmacologically effective agents such as psychomotor stimulants, sedatives, tranquilizers and sedative-level dosages of tranquilizers, etc., as well as buffers and usual pharmaceutical carriers or diluents. Examples of some of these drugs are phenobarbital, sodium phenobarbital, meprobamate, chlordiazepoxide hydrochloride, butaperazine, methamphetamine, amphetamine, dextroamphetamine.

Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually from five milligrams or above and preferably 25, 50, or 100 milligrams or even higher, depending, of course, upon the emergency of the situation and the particular result desired. Five to 50 milligrams appears optimum per unit dose or usual broader ranges appear to be one to 500 milligrams per unit dose. Daily dosages should preferably range from 10 mg. to 100 mg. The active ingredients of the invention may be combined with other pharmacologically active agents as stated above. It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.

The following formulations are representative for all of the pharmacologically active compounds of this invention.

FORMULATIONS 1. Capsules Capsules of 10 mg., mg. and 50 mg. of active ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.

Typical blend for encapsulation Per Capsule, mg.

Active ingredient, as salt 10 Lactose 259 Starch l26 Magnesium Stearate 4 Total 399 Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:

100 mg. per 250 mg. per 500 mg. per

Ingredients Capsule Capsule Capsule Active ingredient,

as salt 100 250 500 Lactose 214 163 Starch 8l 81 47 Magnesium Stearate 4 6 8 Total 399 500 650 In each case, uniformly blend the selected active ingredient with lactose, starch, and magnesium stearate and encapsulate the blend.

2. Tablets A typical formulation for a tablet containing 10.0 mg. of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate.

Per Tablet, mg. 1. Active ingredient 10.0

2. Corn starch 15.0 3. Corn starch (paste) l2.0 4. Lactose 35.0 5. Dicalcium phosphate 132.0 6. Calcium stearate 2.0

Total 206.0

Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water. Granulate the blend with starch paste and pass the wet mass through an eight mesh-screen. The wet granulation is dried and sized through a twelve mesh screen. The dried granules are blended with the calcium stearate and compressed.

What I claim is:

l. A compound selected from dibenz[b,f]azocin-6(5H)- ones having the formula:

3. A compound of claim 1, which is 5-( l-methyl-3-pyrrolidinyl)-1 l,l2-dihydrodibenz[b,f]azocin-6(5H )-one.

4. A compound of claim 1, which is l 1,12-dihydro-5-(3-pyrrolidinyl)dibenz[b,f1 azocin-6( 5H)-one.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORREGTEON Patent No. 3,676,432 I Dated July 11, 1972 lnventofls) Grover Cleveland Helsley It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the abstract, change "dehydro)dibenz[b, fe[azocin6" to read --dehydro) dibenz[b, f]azocin-6-- Column 1, line 2, change "[b,fe]" to --|:b,f]--

Column 5, line 8, change "11, 12-dihydrodibenz1: jazocin" to read -ll,l2-dihydrodibenz[b f]azocin-- Column '4, line 18, change "[10, f]6'( 5H" to read --[b, f]azocin6( 5H)--; line 66, insert- 6 after azocin and before (5H) Column 6, line 56, change to read -Y is selected from "CHg-CH2 and CH:CH, and- Signed and sealed this 9th day of January 1973..

(SEAL) Attest:

EDWARD M.FLETCHER,JR.'

ROBERT GOTTSCH L AttestingOfficer A K Commissioner of Patents ORM PO-1050 (10-69) USCOMM-DC 60376-P69 w u. s. covumum- PRINTING ornc! Ill. o-uc-su 

2. A compound of claim 1, which is 5-(1-benzyl-3-pyrrolidinyl)-11,12-dihydrodibenz(b,f)azocin-6(5H)-one.
 3. A compound of claim 1, which is 5-(1-methyl-3-pyrrolidinyl)-11,12-dihydrodibenz(b,f)azocin-6(5H)-one.
 4. A compound of claim 1, which is 11,12-dihydro-5-(3-pyrrolidinyl)dibenz(b,f)azocin-6(5H)-one. 